Entering the Era of Truly Individualized Antiretroviral Therapy

By Combining Resistance Testing With Drug-Level Monitoring, Providers Will Be Able to Individualize therapy to a Degree Never Previously Possible

By Andrew D. Luber, Pharm.D., and W. David Hardy, M.D.From San Francisco General Hospital

February 2001

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Over the past few years, there has been much speculation and
debate about the potential role of drug-level monitoring in the optimal
medical management of individuals with HIV infection. In its simplest
form, so-called therapeutic drug monitoring, or TDM, can help a clinician
determine if a particular patient is getting a suboptimal or supra-optimal
dose of a particular drug -- and allow the clinician to titrate that
patient's dose accordingly, to maximize efficacy while minimizing
toxicities. In its most sophisticated form -- in which TDM is combined with
resistance testing -- the information obtained from drug-level measurements
and phenotypic assays can enable providers to individualize antiretroviral
therapy to a degree that was heretofore impossible, so that HIV-infected
patients receive what are, for them, the optimal doses of the most
effective drugs.

While the concept of TDM has been effectively used to
treat other disease states, many clinicians are persuaded that the
treatment of HIV infection is too complex to allow for the
individualization of a patient's antiretroviral regimen based upon
circulating drug levels. Pharmacokinetic differences between
antiretroviral classes, inter- and intra-patient variability,
inter-laboratory variability, assay limitations -- and, of course,
less-than-perfect adherence to therapy -- are often cited as drawbacks to the
full clinical application of TDM in combination with resistance testing.

Until quite recently, office-based clinicians had limited access to
laboratories that could measure circulating drug levels or determine viral
phenotypes, and the use of these tests was largely restricted to
research-related activities. Commercial tests are now available, however,
and so are data from a number of recent studies that demonstrate the
potential benefit of TDM in clinical practice. These findings also offer
evidence that the use of plasma drug-level measurements in conjunction
with phenotypic testing provides more useful information that either test
does on its own.

The principles of pharmacokinetics (PK) and
pharmacodynamics (PD) have been used to manage a number of diseases (see "Glossary of Terms"). Our ability to determine optimal drug levels
for compounds such as the aminoglycosides, vancomycin, anti-epileptics,
and theophylline helps us to prescribe effective, non-toxic doses of these
drugs. In each of these instances what we know about the PK and PD of the
individual compounds enables us to use them in the safest and most
effective way.

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Pharmacokinetic and pharmacodynamic principles also
contribute to the management of HIV-infected patients. The steadily
increasing use of therapies based on two protease inhibitors is but the
most obvious example of the role that PK/PD plays in improving the
clinical outcome of antiretroviral therapy.

Clinical Limitations of TDM

While the clinical use of TDM to guide therapy for HIV-infected patients
has been widely discussed, limitations in both laboratory methods and
clinical experience have hindered the widespread adoption of this new
technology (see Table 1). To begin with, the commercial
laboratories that do phenotypic susceptibility testing only report
concentrations that inhibit 50% of the virus -- the so-called IC50 of the
drug. Ideally, of course, clinicians should know what concentrations are
required to inhibit 95% or more of a viral isolate. At present, however,
the limitations of the assays themselves prevent labs from reporting
reliable results at these higher inhibitory values.

Moreover, the currently available drug-level tests only report total drug levels. Given
that it is a drug's non-protein-bound moiety that is its active component,
these tests should ideally report the free-drug level, rather than the sum
of the free-drug and protein-bound drug levels. Before free-drug levels
can be routinely and reliably obtained, laboratory techniques will have to
be improved -- by ultra-filtration of samples, for example. And given that
only 1% of replication-competent HIV is found in the plasma, methods to
assess viral levels within different compartments of the body must also be
developed.

Another practical limitation of TDM arises from the difficulty
of collecting a "true" trough level, or Cmin, from an HIV-infected
individual. This finicky and demanding clinical task requires that a
patient be available for a blood draw at a particular sampling time during
a dosing cycle -- an onerous obligation on the patient's part, and a tedious
and exacting chore for that patient's care providers.

The clinical complexity of obtaining accurate trough levels has led some investigators
to evaluate the feasibility of substituting population-based dosing curves
for individual Cmin measurements (1). These population curves are derived
by obtaining serial blood levels from large numbers of patients over a
standard dosing interval, thereby providing clinicians with mean blood
levels at fixed time points during that dosing cycle. Using this
methodology, a clinician can draw a random blood sample from a given
patient during that patient's dosing cycle, and then compare this level
with the mean for the study population. If the patient's level is low, the
care provider will want to consider increasing the dose; if the level is
elevated, he or she will want to consider lowering the dose.

Researchers evaluating this technique have experienced widely varied clinical results.
While this method permits sampling at any point during the dosing
interval, it is flawed in that in assumes every patient has the same viral
subtype and the same IC50.

The reliability of TDM is also compromised by
concerns about how accurately in-office measurements of circulating drug
levels reflect out-of-office levels. We know that there is an absolute
correlation between adherence to therapy and the success of antiretroviral
regimens (2, 3). What we don't know, with the same degree of assurance, is
how adherent patients actually are. Most of us rely on our patients to
report their degree of adherence to their assigned therapy -- a method of
data-gathering that is notoriously unreliable.

What's more, patients whose compliance falters badly between clinic appointments often comply
scrupulously with their dosing schedule in the days immediately preceding
their next appointment. And because many of the protease inhibitors have
short half-lives, drug levels obtained from these patients in the clinic
will suggest that they are maintaining therapeutic serum concentrations of
these potent agents between visits, when in reality their adherence is so
poor that they rarely achieve the levels necessary to inhibit viral
replication.

In the last analysis, however, the greatest barrier to
applying TDM to the long-term management of patients with HIV disease may
simply be our inability, at this juncture, to extrapolate clinical outcome
from the results of drug-level monitoring. For diseases such as asthma and
epilepsy we have well-defined therapeutic indices for various agents.
Unfortunately, where HIV is concerned, the relationship between a given
dose of a drug, the plasma level that dose produces, and the efficacy -- and
toxicity -- of that dose has yet to be determined for most agents, although
progress is being made.

Measuring Drug Levels

Both serum and plasma drug
levels can be obtained for all of the nucleoside reverse-transcriptase
analogs. It should be recognized, however, that the active component of
this class of drugs is the intracellular triphosphate moiety (4-6), and it
is the intracellular concentration of the drug, not the circulating drug
level, which determines the frequency of dosing, duration of
antiretroviral activity, and clinical efficacy of the nucleoside analogs.
In an ideal world, the serum and plasma levels of nucleoside analogs would
correlate with the intracellular triphosphate concentrations these drugs
achieve, but real-world data suggest that this relationship does not exist
(6, 7).

Furthermore, analyzing blood samples to determine the triphosphate
concentration of a particular nucleoside analog requires highly
specialized laboratory techniques that are not widely available, and this
practical limitation effectively rules out TDM for this drug class, since
serum and plasma levels of these agents provide little useful clinical
information.

Fortunately, plasma levels can be readily obtained for all of
the protease inhibitors, and this information can be applied directly to
the management of seropositive patients. A number of studies have
demonstrated a strong correlation between such pharmacokinetic parameters
as AUC and Cmin and the clinical effectiveness of the protease inhibitors.
With the exceptions of amprenavir and loprinavir, these agents display
relatively short plasma half-lives (8).

A number of small in vitro studies
have suggested that the protease inhibitors possess persistent
antiretroviral activity within cells even when drug levels have fallen so
far that they can no longer be measured (9). These data have yet to be
validated in clinical practice, however. All but one of these agents are
highly protein-bound. As a result, serum concentrations of free,
biologically-active drug that range between 2% and 10%. The exception is
indinavir, which is only 65% protein-bound and has a free component of 35%
(8).

Plasma levels can also be obtained for all of the non-nucleoside
reverse-transcriptase inhibitors, and this information can also be used to
guide treatment. In contrast to the protease inhibitors, the NNRTIs have
long half-lives that result in relatively constant plasma levels. In one
study, plasma drug levels of nevirapine were so constant that it was
possible to predict the twelve-hour AUC using a single time point (10).

Despite these constant levels, wide inter-patient variability in NNRTI
plasma levels has been recorded, and these individual variations have been
found to correlate with clinical failure (11-13). The biggest limitation
to using TDM for the NNRTIs is not their constant plasma levels but rather
their narrow therapeutic index. In situations where a "low" level of one
of these agents has been identified, the clinician may feel constrained
about increasing the dosage to a more effective level out of concern about
the increased risk of toxicity.

Wide inter-patient variability is not
limited to the NNRTIs; it is seen in the AUC and Cmin values of patients
who are taking protease inhibitors, even among those assigned to
ritonavir-enhanced dual-protease-inhibitor-based regimens (14,15). This
finding is particularly likely to encourage the use of TDM -- since it is the
high incidence of inter-patient variability in AUC and Cmin values that
makes it so important to establish whether a particular patient is getting
a true therapeutic effect from the drugs in his or her regimen.

Although intra-patient variability also occurs in TDM, the range of variability is
not wide. Studies involving indinavir (8), amprenavir (16), and nevirapine
(10) have found modest day-to-day variations in drug levels among
HIV-infected patients taking these drugs, but these differences do not
seem to have clinical significance. Less-than-optimal adherence appears to
be the most likely cause of intra-patient variability.

In addition to
inter- and intra-patient variability in circulating levels of
antiretroviral drugs, clinicians should also expect to encounter
considerable variations in the serum and plasma levels obtained through
different laboratories and different assay methods. In a recent study,
eight laboratories in Europe and North America were sent spiked samples of
protease inhibitors in order to assess those laboratories' accuracy within
20% of the reference compound (17). The researchers found that these eight
laboratories were inaccurate anywhere from 14% to 58% of the time,
depending upon which protease inhibitor was evaluated. Work done in our
own labs has shown that variability can exist between serum and plasma,
among different types of matrixes used for standardizing the assay, and
even among different types of reference compounds used to standardize the
assay (18). Given that there are no established guidelines for TDM,
clinicians should be sure that the accuracy of a laboratory's assays has
been validated by an outside agency before sending samples for testing.

Studies of PK/PD show that low levels of certain agents correlate with
impaired viral suppression, increased risk for the emergence of
drug-resistant viral strains, and the potential for a less durable
clinical response. Although these findings are disturbing on their face,
they can -- and should -- be exploited to guide therapy. When patients can be
successfully shifted from the low end of the variability curve to the
upper end of the curve without incurring undue toxicity, the potential
exists to provide those patients with more potent and more durable
antiretroviral therapy.

The Evidence Favoring TDM

Despite the very real limitations described above, TDM can be used to optimize and individualize
the clinical management of HIV-infected individuals. The first trial to
assess PK/PD in seropositive patients, conducted five years ago, measured
the relationship between circulating levels of ritonavir and the
development of resistant viral isolates. Molla and colleagues tallied the
number of viral mutations that emerged each week among patients who were
receiving ritonavir monotherapy (19). An inverse relationship between the
Cmin and development of resistance was observed: the greater the ritonavir
Cmin, the lower the number of resistant viral isolates. In addition,
elevated Cmin values delayed the emergence of multiple mutations in the
viral isolates.

In the last five years the effects of inter-patient
variability on clinical outcome of HIV-infected individuals have been
evaluated. Both total daily drug exposure (e.g. AUC) and
concentration-specific measurements (e.g. Cmin) have been found to
correlate with degree of viral suppression. In a clear demonstration of
the correlation between AUC and efficacy, Murphy et al. evaluated the
relationship between the inter-patient variability of circulating levels
of indinavir and clinical efficacy (20). A total of 24 HIV-infected
patients who were treated with 800 mg of indinavir every 8 hours had
serial blood-level measurements assessed after a seven-day run-in period.
A seven-fold difference in indinavir AUC was observed within this cohort,
and that difference in total daily drug exposure was found to relate
directly to suppression of viremia: the larger the exposure, the more
pronounced the reduction in replication. In addition, the investigators
found a correlation between both Cmin and Cmax values and viral
suppression.

In a similar study, Schapiro and colleagues evaluated the
effects of saquinavir exposure on decreases in viral load (21). A cohort
of 40 HIV-infected individuals who received monotherapy with 3600 to 7200
mg of saquinavir per day had serial blood samples taken after 28 days on
therapy. For each patient, the AUC was plotted against the decrease in
plasma HIV RNA levels from baseline. The authors noted that a strong
correlation was found between drug exposure and decrease in viral load.

Acosta et al. assessed the effects of indinavir concentrations on
antiretroviral activity among 23 HIV- infected patients seen in a
university-affiliated clinic (22). These treatment-naïve patients were
assigned indinavir in combination with two nucleoside analogs, and their
indinavir levels were measured after a standard 800-mg oral dose. When the
investigators compared Cmin values in patients with detectable viral load
measurements (n=9) against Cmin values for those subjects with
undetectable viral loads (n=14), the latter were found to have
significantly higher mean indinavir trough levels (0.55 µM versus 0.07 µM,
respectively; p = 0.007).

These findings led Fletcher and colleagues to
investigate the impact of manipulating individual patient drug levels
(23). In this small trial, 24 antiretroviral-naïve patients with viral
loads greater than 5,000 copies/mL were randomly assigned to open-label,
concentration-controlled therapy (n=11) or standard doses (n=13) of
indinavir, zidovudine, and lamivudine. Some of the patients assigned to
the concentration-controlled arm had their antiretroviral regimens
titrated up to target Cmin concentrations based upon the manufacturer's
mean pharmacokinetic trough data. Both arms were comparable with regard to
baseline viral-load measurements. Dose modifications in the
concentration-controlled arm of the study were necessary to obtain target
levels for 56%, 11%, and 78% of the ZDV, 3TC, and indinavir doses,
respectively (24).

At six months, 91% of the patients in the
concentration-controlled arm achieved undetectable HIV RNA levels (< 50
copies/mL), versus only 69% of the patients in the standard-dose arm. In
addition, patients randomized to the concentration-controlled arm reached
undetectable levels significantly faster than patients who were receiving
standard therapy (110 days versus 176 days; p = 0.056). Given that the
magnitude of viral load decline predicts durability of response, these
data suggest that dosage modifications can affect therapeutic efficacy
and, potentially, improve durability of response.

In addition to improved
antiviral efficacy, elevated drug levels of antiretroviral agents appear
to improve CD4 cell responses. When Fletcher et al. evaluated changes in
CD4 counts from baseline among 19 of the 24 patients in their study, they
discovered that CD4 counts at weeks 52 and 80 correlated significantly
with indinavir Cmax, and to a lesser extent with indinavir Cmin (25). The
authors concluded that both the Cmin and Cmax of indinavir might be
important in determining the virologic and immunologic response to
antiretroviral therapy.

The impact of drug levels on clinical outcome is
not limited to the protease inhibitors. Joshi and colleagues conducted a
retrospective analysis of the relationship between efavirenz Cmin levels
and clinical efficacy among patients participating in five Phase II
clinical trials (12). Among patients with greater than 80% adherence,
treatment failure -- which the investigators defined as the inability to
attain an HIV RNA level below 400 copies/mL -- was found to be roughly three
times as frequent in patients with Cmin values of less than 3.5 µM than it
was in patients with Cmin values greater than 3.5 µM.

These findings support the belief, held by a growing number of experts on HIV infection
and its treatment, that there is a causal relationship between inter-patient differences in circulating drug levels and clinical response to
therapy. The unanswered question, at this point, is whether individual
differences in susceptibility to antiretroviral drugs, and corresponding
differences in the degree of viral suppression that these individual
patients achieve -- differences, that is, in inter-patient pharmacokinetics
and pharmaco-dynamics -- will translate into appreciable differences in drug
levels, and therefore in clinical outcome.

The Merck 069 trial provides us
with a particularly pertinent example of the value of TDM as a potential
indicator, if not a predictor, of clinical outcome. This trial compared
the efficacy of ZDV and 3TC in combination with one of two indinavir
regimens: 2 400-mg capsules three times a day, or 3 400-mg capsules twice
a day (26). Preliminary data on 287 patients after 16 weeks of follow-up
showed equivalent rates of reduction of viral load to less than 400
copies/mL (72% versus 78% for the b.i.d. and t.i.d. dosing regimens,
respectively). However, in an earlier study the Cmin levels of patients
taking indinavir only twice a day were low enough to raise concerns that
those trough levels might be insufficient to inhibit 90% of wild-type
virus -- a situation that can lead to the emergence of drug-resistant viral
strains (27).

And, in fact, an interim analysis of the pharmaco-kinetic
data on the first 87 patients treated for 24 weeks found a significant
divergence between the treatment arms: 91% of the patients who were taking
indinavir three times a day had viral load measurements less than 400
copies/mL, versus only 64% of the patients who were taking indinavir twice
a day. These findings led Merck to stop the trial and recommend that all
patients in the b.i.d. arm be switched back to t.i.d. dosing. These study
data reinforce the concept that pharmacokinetic parameters have a direct
impact on pharmacodynamic responses.

The outcome of the Merck 069 trial was a disappointment not only to the makers of indinavir but to all
patients who take this widely prescribed agent and to all clinicians and
other care providers who treat them -- because if it had proved possible to
take this potent protease inhibitor safely twice a day, an onerous aspect
of indinavir administration -- strict q8 dosing on an empty stomach -- would
have been eliminated. As all of us who treat HIV-infected individuals are
well aware, anything that simplifies a patient's dosing regimen -- by
reducing the number of doses or the number of pills, the dietary
restrictions or the rehydration requirements -- is likely to improve
adherence, and that in turn improves clinical response.

What the Merck 069 trial did demonstrate is the importance of Cmin data as a potential marker
of clinical outcome. The work of Durant et al. emphasizes just how
important such trough measurements are as predictors of clinical response
to therapy. This group assessed the impact of protease-inhibitor trough
levels on HIV RNA changes from baseline in 81 patients who participated in
the Viradapt study (28). Optimal plasma concentrations were defined as
trough levels two-fold or more above the IC95; levels less than two-fold
above the IC95 were categorized as suboptimal concentrations. After 48
weeks, the mean change in viral load from baseline was significantly
greater in individuals with Cmin levels two-fold or more above the IC95: a
1.28 log reduction, compared with only a 0.36 log reduction among patients
with suboptimal concentrations.

The findings of Durant and coworkers have
broad implications for the treatment of HIV infection, because resistance
to specific drugs -- and potential cross-resistance to drug classes -- develops
when Cmin values drop to suboptimal concentrations. Data drawn from
genotypic and phenotypic studies in treatment-experienced patients reveal
that many of these patients evince elevations in IC50 values not just for
agents to which the patients have been exposed but for agents to which
they have not been exposed (29). In therapy-naïve patients, for example,
the protease inhibitor ABT-378 achieves plasma concentrations that are
well in excess of the wild type IC50. When ABT-378 is given to individuals
who have been previously treated with one or more protease inhibitors,
however, the IC50 values are often increased (29) -- although this agent
appears to retain a significant degree of activity against a number of
multidrug-resistant viral isolates (30).

Although ABT-378 does achieve more than adequate plasma concentrations, there is a breakpoint at which
the plasma levels achieved are no longer sufficient to suppress viremia.
In a study conducted by Kempf et al., 93% of the treatment-experienced
patients whose IC50 increase from baseline was less than 10-fold had a
positive virologic response to this new protease inhibitor, as compared
with a 50% response rate in patients whose IC50 increase was greater than
40-fold (29).

A number of recent studies have investigated the effect of
using two protease inhibitors to achieve higher and more consistent serum
concentrations than can be achieved with either drug alone. In most cases,
this strategy has involved the addition of low-dose ritonavir, for
pharmacodynamic rather than pharmacotherapeutic reasons.

Condra and colleagues evaluated the potential role of dual-protease regimens on viral
isolates that demonstrated resistance to one or more of the drugs in this
class (31). This in vitro study compared plasma levels of various protease
inhibitors -- when those agents were given in combination with low-dose
ritonavir -- with protein-corrected IC95 values for both wild-type and
resistant viral isolates. When Cmin values for each protease inhibitor
were evaluated against mutant viral isolates, the combination of indinavir
at the standard dose of 800 mg and ritonavir at a dose of 200 mg appeared
to provide sufficient drug concentrations to overcome even
highly-resistant viral strains. This finding is not altogether surprising,
given that indinavir has the lowest protein-binding rate of all drugs in
this class and therefore is able to inhibit 95% of the viral isolates at
lower serum concentrations than other protease inhibitors.

The authors concluded that combination therapy with indinavir-ritonavir and possibly
amprenavir-ritonavir may provide effective salvage in many instances of
protease-inhibitor failure, even in individuals who have developed
resistance to several drugs in this class. While the in vitro data
compiled by Condra and coworkers suggest that indinavir-ritonavir based
regimens may have activity against highly-resistant viral strains, it must
be emphasized that these encouraging findings have yet to be validated in
clinical trials -- and that even if regimens based on indinavir-ritonavir and
amprenavir-ritonavir do prove clinically effective in some patients with
multidrug-resistant viral isolates, wide inter-patient variability may
limit drug exposure in some patients, thereby affecting virologic
response.

Applying the Evidence to Clinical Practice

No one yet understands why one patient responds well to a given regimen, another has
only a partial response, and a third fails to respond at all to the same
regimen. All care providers who treat seropositive patients have
encountered individuals who are scrupulously adherent to their assigned
antiretroviral regimen but who nevertheless fail to experience a
pronounced or durable antiviral effect from what should be a maximally
suppressive regimen. The critical question is why.

ln situations where poor adherence is
not a contributing factor, there are three critical -- and highly
variable -- factors that influence response to therapy: inter-patient
pharmacokinetic differences; differences among viral subtypes; and
inter-patient variability in immune responses (Figure 1).

Variability in viral subtypes between patients has been an under-appreciated factor in
the management of HIV-infected individuals. We know that treatment-naïve
individuals often display highly sensitive virus, as indicated by very low
IC50 values. We also know that heavily pretreated patients often exhibit
less susceptible viral strains, as evidenced by increased IC50 values. In
addition, recent data have shown that antiretroviral regimens that are not
fully suppressive result in sequential elevations in viral phenotypes
(32). When this information is coupled with the wide inter-patient
variability that is seen whenever plasma levels of protease inhibitors or
NNRTIs are measured, it is apparent that individual patients have
dramatically different levels of exposure to individual drugs, even when
adherence is optimal.

Just how dramatic that difference in exposure can be
is revealed in the phenotypic data obtained from two patients seen in our
clinic. Both of these patients were started on a three-drug regimen of
indinavir plus the coformulation of ZDV and 3TC at the standard doses. The
considerable inter-patient variability in circulating levels of indinavir
was first revealed when we conducted TDM of these two patients -- and found
that Patient A had a trough level of 0.08 ug/mL, whereas Patient B had a
trough level of 0.24 ug/mL on the same dose of indinavir. Using the
PhenoSense® assay, our lab discovered that Patient A had an IC50 of 0.013
µg/mL, while Patient B had an IC50 of only 0.002 µg/mL. Treated for
exactly the same length of time with exactly the same doses of
indinavir -- and with the same degree of compliance -- these two patients
nonetheless manifested significantly different levels of exposure to the
drug: Patient A's trough level was a mere six-fold above the IC50; Patient
B's trough level was 120-fold above the IC50.

These PK/PD differences may
well explain why population-based dosing curves fail to reliably predict
clinical success. Such methods assume that each patient in a given
population has the same virus, and hence the same degree of drug exposure.
As a growing body of scientific evidence indicates, this is almost never
the case. What should be evaluated is not the relationship of a given
sample to a population-based dosing curve, but the relationship of that
sample to the individual patient's viral subtype (Figure 2).

Properly undertaken in a sufficient number of HIV-positive patients, this
comparison will produce a classic bell curve -- one in which "low" drug
level/IC50 ratios have modest antiviral effects, "therapeutic" drug level/
IC50 relationships produce maximally suppressive antiviral responses, and
"excessive" drug level/IC50 relationships result in toxicity, leading to
poor adherence and modest antiviral effects.

When the relationship between therapeutic drug levels and IC50 values has been more fully delineated, it
will in all likelihood reveal two important subgroups under the bell
curve, one fixed and one shifting. The former group will be made up of
those individuals who experience durable, long-term responses to
antiretroviral therapy; the latter, of patients who achieve prompt and
near-complete suppression of viremia, only to have their HIV RNA levels
begin to climb inexorably upward (Figure 3). The critical question that
has yet to be answered is: What level of drug-to-virus exposure is most
likely to predict success or failure?

When phenotyping is combined with TDM,
care providers are able to get a much clearer idea of what is happening at
the cellular level in each patient who undergoes such combination testing.
Take the case of an extensively pretreated patient who was recently
evaluated at our clinic. This individual's phenotypic resistance assay
revealed that he had, over the previous four years, developed
significantly decreased susceptibility to all of the F.D.A.-approved
protease inhibitors. (The patient's decreased susceptibility ranged from a
22-fold reduction in susceptibility to amprenavir to a 171-fold reduction
in susceptibility to nelfinavir.) However, when we compared his IC50 and
Cmin we recognized that we could easily obtain levels well in excess of
this inhibitory concentration using a regimen that combined amprenavir
with low-dose ritonavir.

Evaluating a phenotype without a drug level -- or a
drug level without a phenotype -- fails to provide the clinician with all of
the information he or she needs to properly interpret the results of
either of these tests. This is true of all patients -- because individual
pharmacokinetic responses are so variable, even in treatment-naïve
patients -- but it is especially true of heavily-pretreated patients. In
patients who have been on a succession of antiretroviral
regimens -- monotherapy, dual therapy, and various three- and four-drug
combinations -- multiple codon mutations are the rule, not the exception. In
such patients, elevated IC50 values are the norm, and it is only when the
patient's IC50 is paired with the results of drug-level monitoring that
the amount of actual drug exposure to particular antiretroviral agents can
be determined.

Conclusions

With the advent of commercial tests that measure both plasma drug
levels and susceptibility to therapy, clinicians finally have the tools they
need to evaluate an individual patient's responsiveness to individual antiretroviral
agents, information that can be used to devise truly individualized drug regimens.
We now have drugs that can suppress viral replication to levels so low that HIV RNA
cannot be detected by the most sensitive commercial assays -- and we have the
clinical tools we need to devise patient-specific regimens that will achieve that objective.

The value of the data derived from these new tests will be only as good
as the clinician's ability to interpret those data, of course -- and accurate interpretation
will depend on familiarity with both the advantages and limitations of current methodologies.
As more data are derived -- and as more clinicians gain comfort with the new technology -- significant
advances in our understanding of the clinical implications of information derived from
TDM and resistance testing will undoubtedly occur.

At the moment, these new tests offer us a unique opportunity to evaluate
individual responses to antiretroviral therapies. And this clinical advantage offers us an
opportunity to prevent treatment failures and increase the durability of responses more fully
and more effectively than ever before. We badly need well-designed clinical trials and
broad-based clinical experience to validate these theories and principles. Until such
data are derived, clinicians should interpret the information they obtain from drug-level
tests and phenotypic assays with care. However, our early experience with these new
clinical tools teaches us that these tests provide potentially valuable assistance
in devising antiretroviral regimens that achieve the greatest possible suppression of
viremia with the lowest incidence of therapy-limiting toxicities.

AUC (Area Under the Curve)
The total exposure of a
compound during its prescribed dosing interval. The AUC is
calculated by obtaining serial drug levels during an entire dosing
period, and then determining the total serum concentration of the
drug throughout that period. While AUC does assess total drug
exposure with great accuracy, its use in clinical practice is
limited by the fact that it requires multiple samples over a given
dosing interval.

Cmax
The maximum concentration that a compound achieves during a dosing interval. Given that this value represents maximal exposure to the agent in question, it is often carefully evaluated for potential dose-related toxicities.

Cmin
The minimum concentration that a compound achieves during a dosing interval. This value represents the lowest level of a given drug to which the virus is exposed to during the dosing period, and so it also represents the period in the dosing interval when the likelihood of viral breakthrough is greatest, if concentrations fall to subtherapeutic levels.

Pharmacodynamics
The activity of a specific compound with regard to its uptake, movement, binding, and interactions at the site of pharmacologic activity.

Pharmacokinetics
The patient's ability to handle a specific compound, as measured in terms of absorption, distribution, metabolism, and excretion. Pharmacokinetics and pharmacodynamics are directly related, because the ability of a specific compound to work at a specific site is dependent upon the pharmacokinetics of the individual compound. For example, if an antibiotic is active in vitro against common pathogens in pulmonary infections but the compound doesn't reach the lungs, then the pharmacokinetic parameters of the drug limit it's pharmacodynamic activity. In addition, inter-patient pharmacokinetic differences -- such as differences in absolute bioavailability, protein binding, and/or volume of distribution -- can also significantly alter the pharmacodynamic activity of a given compound.

Therapeutic Index
The difference in drug exposure between the
concentration needed to achieve a pharmacological effect and the
concentration that will cause toxicity. Compounds with a large
therapeutic index can have their doses titrated upward to achieve
maximum effect with little concern about toxicity, whereas compounds
with narrow therapeutic indices need to be titrated with
considerable caution.

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